Innate Immunity and Allergy: Modulation by CTLA4

免疫应答，包括由Toll样受体（TLR）4调节的免疫应答，为适应性变应性免疫应答奠定了基础。 我们的初步数据已经揭示了一种潜在的新的免疫途径，在肺连接TLR 4激活细胞毒性T淋巴细胞抗原4（CTLA 4）的上调。 我们证明CTLA 4信号可以抑制实验性哮喘的过敏反应。 具体来说，我们发现阻断CTLA 4会增加过敏性炎症，而CTLA 4的过度表达会抑制过敏性炎症。两种途径扩展了这些发现。 首先，先天性TLR 4配体在体外和体内均上调CTLA 4并抑制实验性哮喘;与此观察结果一致，具有TLR 4应答缺陷的TLR 4突变小鼠具有增强的过敏应答。 其次，通过CD 45 RB信号增加CTLA 4，降低过敏反应。 由于所有三种分子（CTLA 4、TLR 4和CD 45 RB）都表达于T调节细胞（TlR）上，因此我们将研究TlR在TLR 4和CD 45 RB介导的实验性哮喘抑制中的功能。 有趣的是，我们的初步数据还表明，内毒素成分脂质A，这是一个TLR 4配体，改善实验性哮喘。流行病学研究表明，暴露于富含内毒素的环境可降低儿童哮喘的风险，这与我们的小鼠研究结果一致。 此外，在我们的模型中，体内Treg细胞的耗竭增强了过敏反应并阻断了TLR 4配体介导的实验性哮喘抑制。 这些观察结果表明，TLR 4介导的哮喘抑制是由表达TLR 4的CTLA 4介导的。 因此，我们的假设是TLR 4通过调节CTLA 4的上调来减弱适应性免疫应答，CTLA 4是抑制过敏性炎症的关键途径。目的1将通过确定CTLA 4的抑制（使用抗CTLA 4抗体或缺陷小鼠）如何促进变应性炎症，以及CTLA 4表达的增加如何降低变应性炎症（使用过表达CTLA 4的CTLA 4转基因或CD 45 RB抗体）来表征CTLA 4在抑制变应性炎症中的作用。 目的二是研究TLR 4信号对CTLA 4表达的调节作用。 目的3将确定TLR 4信号抑制变应性炎症的机制，包括细胞成分（APC，T细胞），以及CTLA 4信号是否增强TLR 4诱导的变应性炎症抑制活性。 目的4通过对CTLA 4启动子区的分析，探讨TLR 4和CD 45 RB调控CTLA 4表达的分子机制。 本项目的目的是确定先天免疫调节过敏性哮喘的新途径和潜在的治疗靶点。

The immune responses, including those modulated by Toll-like receptor (TLR) 4 set the stage for the adaptive allergic immune response. Our preliminary data have uncovered a potential novel immune pathway in the lung by linking TLR4 activation with upregulation of cytotoxic T lymphocyte antigen 4 (CTLA4). We demonstrate that CTLA4 signals can inhibit allergic responses in experimental asthma. Specifically, we show that blocking CTLA4 increases allergic inflammation, whereas over expression of CTLA4 suppresses allergic inflammation. Two pathways extend these findings. First, innate TLR4 ligands upregulate CTLA4 both in vitro and in vivo and inhibit experimental asthma; and consistent with this observation, TLR4 mutant mice, which have deficient TLR4 responses, have enhanced allergic responses. Second, increased CTLA4, by CD45RB signals, decreases allergic responses. Because all three molecules (CTLA4, TLR4, and CD45RB) are expressed on T regulatory (Tregs) cells, we will investigate the function of Tregs in the TLR4 and CD45RB mediated inhibition of experimental asthma. Interestingly, our preliminary data also show that the endotoxin component lipid A, which is a TLR4 ligand, ameliorates experimental asthma. Consistent with our murine results, epidemiological studies show that exposure to an endotoxin rich environment decreases the risk of childhood asthma. Furthermore, in our model, the depletion of Treg cells in vivo enhances allergic responses and blocks TLR4 ligand mediated inhibition of experimental asthma. These observations indicate that TLR4 mediated suppression of asthma is mediated by CTLA4 expressing Tregs. Thus, our hypothesis is that TLR4 attenuates the adaptive immune response by modulating upregulation of CTLA4, a critical pathway in the suppression of allergic inflammation. Aim 1 will characterize the role of CTLA4 in the suppression of allergic inflammation by determining how inhibition of CTLA4 (using anti-CTLA4 antibody or deficient mice) promotes allergic inflammation, and how increased CTLA4 expression decreases allergic inflammation (using CTLA4 transgenics that overexpress CTLA4, or CD45RB antibody). Aim 2 will investigate whether TLR4 signals modulate CTLA4 expression in vivo. Aim 3 will determine the mechanisms by which TLR4 signals suppress allergic inflammation, including the cellular components (APC, T cells), and whether CTLA4 signals enhance TLR4-induced suppressor activity in allergic inflammation. Aim 4 will determine the molecular mechanisms by which TLR4 and CD45RB regulate CTLA4 expression in T cells by analysis of the CTLA4 promoter region. The objective of this project is to identify novel pathways, and potential therapeutic targets by which innate immunity modulates allergic asthma.